Therapeutic process using melatonin

ABSTRACT

THE SYMPTONS FO EPILEPSY AND PARKINSONISM ARE RELIEVED BY THE ORAL OR PARENTERAL ADMINISTRATION OF MELATONIN, AND A PSYCHOTROPIC EFFECT IS EXERTED.

United States Patent ABSTRACT OF THE DISCLOSURE Thesymptoms of epilepsyand Parkinsonism are relieved by the oral or parenteral administrationof melatonin, and a psychotropic effect is exerted.

FIELD OF THE INVENTION This invention concerns application of theheterocyclic indole; compound melatonin, Formula I, in a drug,bioaffecting, and body treating process and particularly anencephalotherapeutic process useful in the control of the symptoms ofepilepsy, Parkinsonism, and the psychotherapeutic management of certainmental diseases 011.0- onzonznno 0 on3 DESCRIPTION OF THE PRIOR ARTParkinsons disease is a motor incapacitating disease characterized byrigidity and tremor of the limbs. The disease, has been treated mainlywith anticholinergic compounds. Response is variable and dosage must becarefully adjusted for each patient. At best control of the symptomshasbeen only moderately successful. More recently experimental use has beenmade of L-dihydroxyphenylalanine (L dopa) which promises to offer asubstantial improvement over the anti-cholinergic agents in managementof the disease. The dose required with L- dopa' is quite high, however,and many undesirable side effects accompany treatment. Accordingly,further therapeutic improvement is desirable.

Similarly 'with epilepsy, management of the symptoms has depended mainlyupon the use of anti-convulsant drugs and sedatives such asdiphenylhydantoin and phenobarbital. 'Response is quite variable anddosage with several drugs in combination is frequentlyy necessary toachieve any improvement.

Melatonin, the substance which has now been found to .be useful in themanagement of the foregoing conditions, is a hormone secreted by thepineal gland. It is a known compound which has been associated with thepineal gland since its identification as the pineal hormone in 1959(Lerner and Case, J. Am. Chem. Soc. 81, 60845 (1959)). Althoughsubstantial biochemical and physiological research on the pineal glandand melatonin has been conducted during the last years, noclinicallyuseful method of therapy based upon the knowledge developed has yet beensuggested. The acute pharmacology of the compound has been described byBarchas et al., Nature 214, 912-20 (1967). Pharmacological studies withit were previously reported by Gessner et al., Nature 190, 179-80(1961), particularly with respect to the actions on. smooth muscle,blood pressure, and behavioral activity in the rat. The compound hasbeen reported to have hypnotic action on rats, but otherwise to be quiteinert pharmacologically and to be non-toxic. In a study of the toxicityof melatonin in mice, the compound failed to produce death at doses upto 800 mg./kg. The-LD on injection Formula I ice could not be determinedsince sufliciently concentrated solutions could not be prepared topermit injection of a toxic dose. The most prominent biological actionof melatonin previously known is its ability to lighten the color of thefrogs skin (melanophore contractor).

SUMMARY OF THE INVENTION The present invention involves the systemicadministration by the oral or parenteral routes of an effective nontoxicdose ofmelatonin where it is desired to control the symptoms ofepilepsy, Parkinsons disease, and some mental diseases. Administrationof the substance exerts a marked calming effect on patients and causeschanges in the electroencephalogram. Generally a period of sleep followsadministration of the drug, but other desired effects are sustained fora considerable period after the subject awakens. In normal as well aspatients suffering from epilepsy and Parkinsonism the EEG reflects anincrease in alpha rhythm and with epileptics the paroxysmal activity issubstantially diminished or eliminated. In Parkinsonism a promptdiminution of muscle tremor occurs and after daily administration forseveral days marked reduction in rigidity with a concomitant increase inmotor ability takes place.

Administration of melatonin is substantially without undesired sideeifects. The substance is well absorbed, well tolerated, andsubstantially non-irritating to the tissues and gastrointestinal tract.Subjective comments by normal individuals to whom the drug has beenadministred suggest that a rather pleasant sensation is involved.Following a normal sleep the patient is easily awakened and reports afeeling of comfort and well being. No impairment of alertness orjudgment results. The effects reported are desirable for the managementof patients having behavioral disorders such as manic depressivepsychosis, senile dementia, and presenile dementia which are manifestedby either agitation or depression since the drug has a claming effectyet induces a feeling of elation.

Dosage is in the range of 0.5 to 2.0 g. per day, preferably divided intotwo or three units. The preferred dose is -1 g. per day orally. Lowerdoses can be effectively used, particularly when administeredintravenously. The lowest dose found effective was 0.25 mg./kg. of bodyweight intravenously. Stated generally the applicable dosage range forthe management of each of the conditions with which the invention isconcerned is 0.25 to 30 mg./kg. of body weight per day. It is preferredto administer the substance by the oral route, but in emergencysituations where quick action is needed, intravenous administration isused. The latter is also preferred for patients who cannot or refuse toaccept oral medication. Other parenteral routes may be used.

For intravenous administration, a solution in 1% aqueous, ethanol isemployed. For other parenteral routes solutions or suspensions in otherparenteral liquid vehicles such as peanut oil are applicable. For oraluse, flavored suspensions or solutions may be employed, but tablets andcapsules are generally adequate and are preferred.

DESCRIPTION OF THE PREFERRED EMBODIMENTS Example 1 Psychotropicaction-Graded doses of melatonin ranging from 0.25 mg./kg. of bodyweight to 1.25 mg./ log. of body weight were administered by intravenousinjection of solutions in 1% aqueous ethanol to five healthy volunteersin consecutive fashion. All subjects were studied by poligraphic recordsof parieto occipital electroencephalogram (EEG), respiration, andelectrocardiogram (EKG). After the effects of the dose on one subjectwere evaluated, the next higher dose was administered to the nextsubject. At all doses practically the same effects were found althoughthey become more apparent with the largest dose. In no case wereundesirable etfects observed. Five additional volunteers were thentreated with an intravenous dose of 1.25 mg./kg. of melatonin.Poligraphic records were prepared as before. Shortly afteradministration of this dose the EEG activity was characterized by slightdeactivation. Fifteen to 20 minutes later the subjects fell asleep. Theyare easily awakened 45 minutes later. Most of them related that they hadhad vivid oniric episodes while asleep. In the following hour EEGactivity was continuously monitored. During this time the EEG showed anincrease in percentage and amplitude of alpha rhythms. As an objectivemeasure of the subjects mental alertness and capacity they were requiredto estimate the duration of a 10 second interval 1 hour after treatmentand the results were compared with those obtained in a similar testadministered to them before treatment. Their average estimate was1122:025 seconds before treatment and 11.10* 0.34 seconds 1 hour aftertreatment. In a similar test when the volunteers were permitted tolisten to their own heart rhythm as a reference, the average 10 sec.time estimates were 1034:022 seconds before treatment and 10.441-033seconds 90 minutes after treatment. The data is arranged in Tables I andII. As a further objective measure of the effect of the drug on mentalactivity reaction times were measured before, and 90 minutes aftertreatment with melatonin as above. Reaction time was measuredelectronically as the elapsed time between lighting a light in front ofthe patient and his pressing a button after seeing the signal. Nosubstantial change in reaction time resulted from the treatment. Theaverage reaction time for the 10 subjects before treatment was233.771-103 msec., and 90 minutes after treatment, 272.4:118 msec. Atthe end of 2 hours the experiment was concluded. At this time thesubjects reported that they felt a sensation of well-being, comfort, andelation.

TABLE I.EFFECT OF MELATONIN ADMINISTRATION OF 10 SECOND TIME ESTIMATE[No reference signal] Volunteer dose N0. MgJkg. Control Melatonin PTABLE IL-EFFECT OF MELATONIN ADMINISTRATION ON 10 SECOND ESTIMATE [Pulseas reference signal] Volunteer dose MgJkg. Control Melatonin P X 10.34i0. 2O 10. 44:1;0. 33

Example 2 Epilepsy treatment.A patient, age 24 years, female, sufferingfrom grand mal and temporal lobe epilepsy of 21 years duration and undertreatment with sodium hydantoinate 300 mg. per day, carbamazepine 600mg. per day, and phenothiazine mg. per day, was treated with a singledose of 0.25 mg./kg. of melatonin intravenously as a solution in 1%aqueous ethanol. A second patient, age 26, male, suffering from grandmal, myoclonic seizures, temporal lobe seizures and dementia of 17 yearsduration, and under treatment with sodium hydantoinate 300 mg. per daywas treated similarly with a single dose of 1 mg./kg. of body weight ofmelatonin intravenously. In each of these patients changes similar tothose observed in the healthy volunteers described in Example 1occurred. In addition EEG changes indicating a depression of theparoxysmal activity during the first 4 hours after melatonin treatmentwere observed. One of these patients who was normally reactive tohyperventilation enjoyed a blockage of this reactivity as a result ofthe melatonin treatment.

Example 3 Epilepsy treatment.A 27 year old female suffering from grandmal, petit mal, myoclonic seizures, focal temporal lobe seizures, mentaldeficiency and secondary schizophrenia-like psychosis of 13 yearsstanding was under treatment with sodium hydantoinate 100 mg. per dayand diazepam 10 mg. per day. This treatment was discontinued for aperiod of five 'days before treatment with melatonin was initiated. Onthe first day of treatment, 60 mg. of melatonin was administeredintravenously as a solution in 1%v aqueous ethanol, and on each of thesecond and third days 30 mg. was administered intravenously. Thefollowing electroencephalographic activity was observed on the first dayfollowing the 60 mg. dose.

(A) Control record-The activity was characterized by the presence ofspikes and sharp waves. The spike activity appeared in the amygdaloidnuclei and was projected to both hippocampus and temporal cortices.

(=B) Eleven minutes after melatonin administration the spike activitywas replaced by slow theta trains in both cortices. The patient becamesomnolent and fell asleep 7 min. later. i

(C) Manifestation of rapid eye movement occurred during sleep and adecrease of the amplitude and frequency of the theta trains wasobserved. p

(D) The patient awoke after 50 minutes and the theta hippocampal trainsreappeared. The background activity had a lower amplitude. Theseconditions continued for 220 minutes. 1

(E) At this point, trains of 15 to 25 c.p.s. appeared intercalated.

(:F) Three hundred minutes after melatonin administration, the recordshowed a regulation of the activity with complete disappearance of theparoxysmal graphoelements.

During the second and third days, when the patient received 30 mg. ofmelatonin per day, the EEG showed a diminution of the paroxysmalgrapholements.

Example 4 Treatment of Parkinsons disease-An adult male patientsuffering from Parkinsons disease of 4 years duration who had beentreated previously with anti-ch0 linergic agents was withdrawn from alltherapy for 5 days. During this period a panel of three physiciansindividually evaluated the patient with respect to rigidity, tremor, andmotor ability. Melatonin, mg., divided into 2 doses daily wasadministered intravenously as a solution in 1% aqueous ethanol for aperiod of 1 week. On the third day of treatment the patient was againevaluated by the three physicians. At this time only slight diminutionin rigidity had occurred, but the tremor had been substantiallyabolished. Motor ability had not substantially improved. At the end ofthe first week intravenous treatment was terminated and oral treatmentwas commenced at the rate of see mg. per day divided into 3 doses. Bythe middle of the second week of treatment (third day of oral treatment)evaluation by the same panel of physicians revealed approximately 65%reduction in rigidity, 80% reduction in tremor, and a 20% improvement inmotor ability. Oral treatment according to this regime was continuedthrough the second and third Weeks. The reduction in rigidity and tremorwas maintained, and by the end of the third week motor ability hadimproved to 70% of normal. In the fourth week treatment with a placeboWas substituted for the melatonin. After several days of treatment withthe placebo rigidity and tremor increased and motor ability began todeteriorate. Measurement of the EEG following the initial dose ofmelatonin revealed that within 11 min. there was a decrease in amplitudein the EEG and that muscle tremor diminished. Tremor was measured bothat rest and when the subject was attempting to button his coat, thelatter being referred to as maximum tremor. Maximum tremor was usuallyfound to diminish within 18 min. after dosage with melatonin during thecourse of therapy. Within 38 to '67 min. after melatonin treatmenttremor was practically abolished and a distinct alpha rhythm was seen inthe EEG.

What is claimed is:

1. A process which comprises administering orally or parenterally to apatient suffering from behavioral disorder or epilepsy or Parkinsonsdisease an effective non-toxic dose of melatonin.

2. The process of claim 1 wherein a daily dose of from 0.25 to 30mg./kg. of body weight of melatonin is administered.

3. A process according to claim 1 wherein a daily dose of from 0.25 to30 mg./ kg. of body weight of melatonin is administered to a patientsulfering from epilepsy.

4. A process according to claim 1 wherein a daily dose of from 0.25 to30 mg./kg. of body weight of melatonin is administered to a patientsuffering from Parkinsons disease.

5. A process according to claim 1 wherein a daily dose of from 0.25 to30 mg./kg. of body weight of melatonin is administered to a patientsuifering from a behavioral disorder.

References Cited Barchas et al., Nature, 214, 912920 1967). Gessner etal., Nature, 190, 179-180 (1961).

STANLEY J. FRIEDMAN, Primary Examiner UNITED STATES PATENT OFFICECERTIFICATE OF CORRECTION Patent No. 3,642,994 Dated February 15, 1972Inventor (s) Fernando Anton-Tav It is certified that error appears inthe above-identified patent and that said Letters Patent are herebycorrected as shown below:

Col. 1, 1. 49 "frequentlyy" should be "frequently" Col 1, 1. 63 I "912"should be .9929" Col. 2, l. 39 "claming" should be "calming" Col. 3, l.51 "8" (First No. 8) should be "7" Col. 3, 1. 55 After "X" insert andinsert I X before "11.10"

Col. 3, l. 70 After "X" insert and insert x before "10.44"

Col. 4, l. 49 Delete "c.p.s." and insert cps Col. 4, l. 57"grapholements" should be "graphoelements" References cited:

Col. 6, l. 19 "912" should be "919" Signed and sealed this 1st day ofAugust 1972.

(SEAL) Attest':

EDWARD M-FLETCHER ,JR. ROBERT GOT'I'SCHALK Attesting OfficerCommissioner of Patents FORM PO-105O (10-69) USCOMM-DC 60376-P69 U.5,GOVERNMENT PRINTlNG OFFICE: I969 O-366-334

